Dendritic cells (DCs) are professional antigen presenting cells (APC) which play a central role in the induction of innate and adaptive anti-viral immune responses. DCs are generally divided into two groups: "myeloid" DCs (mDCs), e.g. Langerhans cells, dermal DCs, blood CD11c+ cells, and those which morphologically resemble plasma cells e.g. plasmacytoid DCs (pDCs). pDCs have been implicated on the front lines of defense against pathogens. Upon contact with enveloped viruses or microbial products, they produce extraordinarily high levels of type I interferons, a spectrum of inflammatory cytokines and polarize allogeneic CD4+ T cells into Th1 cells, pDC frequencies decline in HIV-1 infected individuals, a trend that inversely correlates with susceptibility to opportunistic infections. Likewise, abrogation of pDC function in animal models renders them susceptible to infection with MCMV. Recent studies, while controversial, indicate that pDCs are productively infected by HIV, suggesting that these cells perpetuate infection. In contrast, we found that pDCs (but not myeloid DCs or mDCs), undergo maturation, produce type I interferons and TNFa, and resist apoptosis after exposure to HIV. In addition they activate T cells and induce the bystander activation of maturation of mDC. These data indicate that pDCs assume much more of an anti-viral role than previously considered. This proposal will further define the role of pDCs in the induction of anti-HIV immunity. The specific aims are to: (1) characterize the nature and consequences of the pDC-HIV interaction in terms of receptors utilized, the cytokine and chemokine profile of infected pDCs and the relevance of this interaction in vivo; (2) determine whether highly purified pDCs support highly productive HIV replication and/or transmission to T cells, and, (3) establish whether pDCs can process and present physiologically relevant sources of HIV antigens to CD4+ and CD8+ T cells. These pre-clinical studies will provide the basis for future trials to test the immunomodulatory capacity of pDCs in chronic HIV infection.